From Cell Division to Life: The Journey of Folic Acid

Folic acid is the synthetic, laboratory-produced form of vitamin B9, a water-soluble member of the B-vitamin group. The human body cannot synthesize folic acid naturally; therefore, it must be obtained through diet or supplements. The naturally occurring form in foods is called “folate,” which exists in various biologically active molecular types (e.g., 5-methyltetrahydrofolate).
The term "folic acid" generally refers to the stable, synthetic form known as pteroylmonoglutamic acid, found in medications and supplements. In contrast, natural folates are more fragile and can easily degrade during cooking, processing, or storage.
The molecular formula of folic acid is C₁₉H₁₉N₇O₆, and its structure includes a pteridine ring, para-aminobenzoic acid (PABA), and glutamic acid.

Derived from the Latin word folium, meaning “leaf,” folic acid was first isolated from spinach in 1941 under the leadership of medical researcher Dr. Lucy Wills. Industrial synthesis of folic acid was developed in 1945, and the compound demonstrated a rapid hematological response in most cases of macrocytic anemia.

Folic acid plays a crucial role in cell metabolism, particularly in reactions involving the transfer of one-carbon units. Therefore, it is involved in several critical physiological processes, including DNA synthesis, amino acid metabolism, cell proliferation, and nervous system development.

Folate acts as an essential coenzyme in the synthesis of purine and thymidine bases. Specifically, the 5,10-methylenetetrahydrofolate form catalyzes the conversion of dUMP to dTMP via the enzyme thymidylate synthase. This step is indispensable for DNA replication and is necessary for DNA synthesis and cell division. In cases of deficiency, the cell nucleus cannot mature properly, leading to the formation of megaloblastic cells. Folic acid serves as a methyl group donor in the conversion of homocysteine to methionine. Vitamin B12 acts as a cofactor in this reaction. This transformation is crucial for the production of S-adenosylmethionine (SAM), the universal methyl donor in methylation reactions. Folic acid is also involved in the metabolism of serine, glycine, and histidine, and is essential for epigenetic regulation and gene expression. It regulates homocysteine levels. Elevated homocysteine levels can cause inflammation and endothelial damage in blood vessels. By enabling the conversion of homocysteine to methionine, folate helps reduce circulating homocysteine levels. In this way, it plays an important role in the prevention of cardiovascular diseases. Folic acid plays a critical role in the development of the nervous system, especially during the embryonic period. Neural tube closure occurs during the 3rd and 4th weeks of pregnancy, and folate requirements are at their highest during this stage. Folic acid is effective in preventing neural tube defects (such as spina bifida and anencephaly). It also plays a role in myelin synthesis and indirectly contributes to the synthesis of neurotransmitters such as serotonin, dopamine, and norepinephrine. If we classify the active roles of folic acid forms, we get the following table:

Folate deficiency can impair several physiological processes, particularly nucleic acid synthesis, amino acid metabolism, and cell proliferation, leading to diseases affecting multiple systems. The deficiency may arise due to inadequate intake, increased demand, malabsorption, or the use of antagonistic drugs.

Megaloblastic anemia is a type of anemia characterized by the production of large, immature, and abnormal red blood cells (megaloblasts) in the bone marrow due to impaired DNA synthesis. Folate deficiency is a known cause of this condition.
The disease occurs when folate deficiency impairs thymidine synthesis, preventing nuclear maturation and leading to the enlargement of erythrocyte precursors without their division.
Symptoms include fatigue, weakness, pallor, palpitations, concentration difficulties, and glossitis—marked by a burning sensation and redness of the tongue.

Globally, megaloblastic anemia due to folate deficiency is common, especially in low- and middle-income countries. According to the World Health Organization (WHO), the global prevalence of anemia exceeds 30%, with a significant portion attributed to folate deficiency. Among pregnant women and children, folate deficiency anemia ranges between 20% and 40%.

The neural tube is the embryonic structure that develops into the brain and spinal cord. Neural tube defects are congenital anomalies that result from the failure of this structure to close during embryonic development. The most common forms include spina bifida and anencephaly. Insufficient folate disrupts cell proliferation and DNA synthesis, resulting in improper closure of embryonic neural tissue. Postnatal symptoms may include open spinal nerves (spina bifida), underdevelopment of the brain (anencephaly), hydrocephalus, and paralysis.

Neural tube defects occur in approximately 0.5 to 2.0 per 1,000 live births worldwide. Before the widespread use of folic acid supplementation, the prevalence in many countries was around 1 per 1,000. Supplementation has reduced this rate by 50–70%.

Homocysteine is an intermediate in methionine metabolism and is normally remethylated back to methionine with the help of folic acid. In folate deficiency, this remethylation process is impaired, leading to elevated blood homocysteine levels.
High homocysteine concentrations can damage the endothelial lining of blood vessels, promoting the development of atherosclerosis. Over time, this increases the risk of cardiovascular diseases such as heart attack, stroke, and deep vein thrombosis.
Although often asymptomatic, elevated homocysteine levels can contribute to serious vascular diseases later in life.

During pregnancy, the demand for folic acid increases. Inadequate intake during this period can lead to complications for both the mother and the fetus.
Folate deficiency may result in miscarriage, preterm birth, placental abruption, and preeclampsia in the mother, while the fetus may experience low birth weight and intrauterine growth restriction.
Sufficient folate intake in the early months of pregnancy is crucial in preventing these outcomes.

Folate plays essential roles in neural cells, including methyl group transfer and neurotransmitter synthesis. A deficiency disrupts methylation processes and reduces the production of neurotransmitters such as serotonin and dopamine.
This can lead to depression, anxiety, memory impairment, and cognitive slowing. Prolonged deficiency may even cause dementia-like symptoms. Therefore, especially in elderly individuals, regular monitoring of folate levels is important.

Folate is vital for the renewal of rapidly dividing cells. As a result, early signs of deficiency often appear in the mouth and skin. Common findings include cracks at the corners of the mouth (angular stomatitis), burning, redness, and swelling of the tongue (glossitis), aphthous ulcers, and mucosal sensitivity. Skin manifestations may include pallor, dryness, and pigmentation disorders due to folate deficiency.

Pregnancy, particularly in its early stages, is a critical period in which the mother’s nutritional status plays a vital role in the healthy development of the fetus. Folic acid is an essential vitamin that ensures the proper closure of the embryonic neural tube. Neural tube defects (NTDs) are serious congenital anomalies resulting from incomplete closure of the embryonic structure that forms the brain and spinal cord. The role of folic acid supplementation in preventing such birth defects—especially spina bifida and anencephaly—has been proven in numerous clinical studies. A landmark study by Czeizel and Dudas (1992) demonstrated that folic acid intake before conception and during early pregnancy can reduce the incidence of neural tube defects by up to 70% (Czeizel & Dudas, 1992).
Health authorities such as the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) strongly recommend folic acid supplementation for women planning to become pregnant. These recommendations are considered among the most fundamental preventive measures for a healthy pregnancy and a healthy baby.

Folic acid naturally occurs in many green leafy vegetables (such as spinach, broccoli, lettuce), legumes (like chickpeas, lentils, and beans), citrus fruits, and whole grains. However, meeting the daily folate requirement solely through natural foods can be challenging, as folate is sensitive to heat and light, and can degrade during cooking.
For this reason, many countries have adopted mandatory or voluntary folic acid fortification of foods. The recommended daily intake of folate for an average adult is approximately 400 micrograms. During pregnancy, this requirement may increase to 600 micrograms.
Inadequate folate intake—especially before conception and in the first trimester—can negatively affect both maternal and fetal health. Therefore, in addition to a balanced diet, folic acid supplementation plays a crucial role.

The use of folic acid supplements during pregnancy is essential, particularly in reducing the risk of neural tube defects. For healthy women—especially those planning pregnancy or in the early stages of pregnancy—a daily supplement of 400 micrograms of folic acid may be recommended.
This recommendation is particularly important for women at high risk of folate deficiency or those with a history of pregnancies affected by neural tube defects, rather than being directed at the general population. In Turkey, folic acid testing is widely available through both public and private laboratories as part of standard medical evaluations. The test, typically performed after 6–8 hours of fasting, provides a clear measurement of serum folate levels. The reference range is generally 4–20 ng/mL. In cases of suspected clinical conditions—such as anemia, pregnancy, or neurological symptoms—this test is covered by the Social Security Institution (SGK). While some debates focus on the potential side effects of excessive folic acid intake, the current scientific consensus affirms that folic acid supplementation at recommended doses is both safe and beneficial. On the other hand, individuals with a healthy, balanced diet and no risk factors may not need supplements; however, folic acid use during pregnancy is widely recommended by most healthcare professionals.

Although the terms “folate” and “folic acid” are often used interchangeably, they differ in terms of chemical structure and biological effects. Folate is the naturally occurring form of vitamin B9 found in foods and can be directly utilized by the body. Folic acid, on the other hand, is a synthetic form used primarily in supplements and food fortification.

The body converts folic acid into its active form through metabolic processes, with the enzyme methylenetetrahydrofolate reductase (MTHFR) playing a key role in this transformation. In certain individuals, reduced MTHFR enzyme activity can impair the efficacy of folic acid.

While folic acid is preferred in supplements due to its stability and bioavailability, folate is the form obtained from natural food sources. Both forms are important in daily nutrition. Today, folic acid supplementation is widely used in public health programs to prevent folate deficiency, especially in the preconception and pregnancy periods.

The MTHFR Polymorphism and Its Relationship to Folic Acid

The activation of folic acid in the body requires a series of metabolic processes facilitated by specific enzymes. One of the most critical steps is catalyzed by the methylenetetrahydrofolate reductase (MTHFR) enzyme, which converts folic acid into its biologically active form, 5-methyltetrahydrofolate (5-MTHF). However, genetic polymorphisms in the MTHFR gene, such as C677T and A1298C, can reduce enzyme activity and slow this conversion process. In individuals with the homozygous form of the C677T variant, MTHFR activity may decrease by up to 30–70%. This genetic variation can lead to impaired homocysteine metabolism, increasing the risk of hyperhomocysteinemia, a condition associated with cardiovascular diseases, neural tube defects, and certain neurological disorders.

In individuals with MTHFR polymorphisms, supplementing directly with the active form, 5-MTHF, rather than synthetic folic acid, may be more effective. This highlights the growing importance of personalized nutrition and genetic testing in modern healthcare.

Research on folic acid is no longer limited to the prevention of deficiency-related diseases. Contemporary studies are increasingly focused on the potential risks of excessive folic acid intake. One major concern is the accumulation of unmetabolized folic acid (UMFA) in the bloodstream, particularly with high supplemental doses. This accumulation has been linked in some studies to potential effects on the immune system, cancer risk, and neurological health (Bailey & Ayling, 2009). However, evidence in this area remains inconclusive, and a clear threshold for toxicity has yet to be established.

On the other hand, mandatory folic acid fortification of foods has been shown to significantly reduce the incidence of neural tube defects in the general population, as evidenced by epidemiological data from countries such as the United States and Canada. Nonetheless, some European countries have been reluctant to implement mandatory fortification policies due to uncertainties about the long-term effects of high folic acid intake. Emerging research is also examining the role of folic acid in epigenetic regulation. Through DNA methylation, folate influences gene expression, potentially exerting effects that begin in embryonic development and persist throughout fetal life. Folic acid is an invisible epigenetic orchestra conductor that silently shapes your genetic destiny. As such, folic acid is now viewed not only as a vitamin but also as a modulator of gene expression, placing it at the core of the fetal programming concept in developmental biology.